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WO1993008258A1 - Appareil et procede ameliores concernant la separation de cellules - Google Patents

Appareil et procede ameliores concernant la separation de cellules Download PDF

Info

Publication number
WO1993008258A1
WO1993008258A1 PCT/US1992/008988 US9208988W WO9308258A1 WO 1993008258 A1 WO1993008258 A1 WO 1993008258A1 US 9208988 W US9208988 W US 9208988W WO 9308258 A1 WO9308258 A1 WO 9308258A1
Authority
WO
WIPO (PCT)
Prior art keywords
column
fluid
signal
responsive
stirbar
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1992/008988
Other languages
English (en)
Inventor
Randal A. Goffe
George Blat
Michael D. Emde
Fred Mill
Patrick M. Maloney
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CellPro Inc
Original Assignee
CellPro Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by CellPro Inc filed Critical CellPro Inc
Priority to JP5507895A priority Critical patent/JP2774195B2/ja
Priority to EP92923299A priority patent/EP0610391B1/fr
Priority to DE69215381T priority patent/DE69215381T2/de
Publication of WO1993008258A1 publication Critical patent/WO1993008258A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5002—Partitioning blood components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/45—Magnetic mixers; Mixers with magnetically driven stirrers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M47/00—Means for after-treatment of the produced biomass or of the fermentation or metabolic products, e.g. storage of biomass
    • C12M47/02—Separating microorganisms from the culture medium; Concentration of biomass
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • G01N33/491—Blood by separating the blood components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/20—Measuring; Control or regulation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/02—Devices for withdrawing samples
    • G01N1/10—Devices for withdrawing samples in the liquid or fluent state
    • G01N2001/1062—Sampling under constant temperature, pressure, or the like
    • G01N2001/1081—Storing samples under refrigeration
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N11/00—Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties
    • G01N2011/0046—In situ measurement during mixing process
    • G01N2011/0053—In situ measurement during mixing process using ergometry; measuring power consumption
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
    • G01N35/04—Details of the conveyor system
    • G01N2035/0439—Rotary sample carriers, i.e. carousels
    • G01N2035/0453—Multiple carousels working in parallel
    • G01N2035/0455—Coaxial carousels
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N2035/1027—General features of the devices
    • G01N2035/1034—Transferring microquantities of liquid
    • G01N2035/1039—Micropipettes, e.g. microcapillary tubes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/808—Optical sensing apparatus

Definitions

  • the present invention is directed in general toward methods and apparatus for selecting target particles from a sample fluid and, more particularly, toward improved apparatus for controlling the operation of a device for performing ⁇ nmunoselection of target cells.
  • Various methods and devices exist for separating component parts of a sample fluid to obtain target particles include filters, centrifuges, chromatographs, and other well-known fluid separation methods.
  • Such immunoselection methods have been used to either positively or negatively select target cells, wherein positive selection refers to the direct selection and recovery of specific target cells, while negative selection refers to the elimination of a specific target cell subpopulation from a heterogeneous population of cells.
  • a column has an entrance end, an exit end, and a substrate positioned intermediate the entrance and exit ends.
  • the sample fluid is provided to the entrance end of the column and is moved through the column under pressure.
  • the substrate separates the target particle from the fluid composition so that the target particle exiting the column will be substantially pure.
  • the target particle exiting the column is collected and retained as the collected product of the separation. Accordingly, the substrate is selected for a particular separation to separate the target particle from the sample fluid.
  • Various substrates exist for use with columns to separate the target particle from the sample fluid.
  • the type of substrate selected for performing the separation will determine how the target particles are separated from the sample fluid.
  • the sample fluid is forced through the column under pressure using a solvent solution.
  • the substrate is selected so that the target particles exhibit substantially different binding characteristics with the substrate than the remaining components of the sample fluid so that the time necessary for the target particles to pass through the substrate will be substantially different from the time necessary for the remaining components of the sample fluid to pass through the substrate. Accordingly, a substantially pure composition of the target particles will exit the column at apredete ⁇ nined time for collection.
  • the substrate may contain beads that have been coated with a ligand, such as an antibody, immobilized on the surface of the beads.
  • a ligand such as an antibody
  • the Iigands are selected to bind with the target particles, thereby immobilizing the target particles within the column.
  • the target particles can be liberated from the beads using various techniques.
  • the target particles are liberated from the beads by gently agitating the beads to break the bond between the target particles and the immobilized ligand.
  • existing columns for performing immunoadsorption have proven undesirable since they have failed to provide commercially acceptable apparatus for agitating the substrate to aid in liberating the target particles.
  • the prior art devices have also failed to provide apparatus for controlling the amount of agitation provided to the substrate, to prevent damage to the target particles and are further undesirable for this reason.
  • column separation devices and particularly other column immunoadsorption devices, have also proven inefficient since these devices require considerable intervention from the operator to control the introduction of the sample fluid to the column as well as controlling the withdrawal of the target particle from the column.
  • column separation devices must be actively monitored through various stages including stages for cleansing the column prior to introduction of the sample fluid and stages for passing the sample fluid through the column. These stages generally require significant intervention from the operator to perform each of the foregoing steps of the fluid separation process, and to perform substeps within these steps. Accordingly, the efficiency of these devices is necessarily limited by the skill and effectiveness of the operator controlling the process. It is desirable, therefore, to provide apparatus for performing fluid separation that minimizes the amount of intervention necessary from an operator of the apparatus. Additionally, it is desirable to provide apparatus for performing fluid separation wherein the movement of fluid through the apparatus may be precisely controlled by the separation apparatus without significant intervention by the operator.
  • an improved fluid control system for use with a cell separator having a column assembly.
  • the column assembly includes a column for separating target cells from a sample fluid.
  • the column assembly also includes a fluid collection bag for subsequently receiving the target cells from the column.
  • the fluid control system includes a column sensor for providing a column signal indicative of the optical density of fluid flowing out of the column and into the fluid collection bag.
  • the fluid control system also includes a column valve responsive to a column valve control signal for selectively enabling the fluid coming out of the column to flow into the fluid collection bag.
  • a data processor is provided for controlling the operation of the fluid control system. The data processor is responsive to the column signal for providing the column valve control signal to optimize the concentrations of the target cells being collected.
  • the column assembly includes a sample fluid supply bag for providing the sample fluid to the column and fluid tubing for coupling the column to the sample fluid supply bag and the fluid collection bag.
  • the fluid control system further includes a pressure sensor coupleable to the column for determining the pressure of the fluid in the column.
  • the pressure sensor includes a connector for coupling a pressure signal to the data processor.
  • a pump is provided and is responsive to a pump control signal for controlling the speed and direction of fluid flow in the fluid tubing.
  • the data processor is responsive to the pressure signal for providing the pump control signal to increase and decrease the pressure of the fluid in the column.
  • a cell separator is provided that includes a column assembly for separating target cells from a sample fluid.
  • the column assembly mcludes a column, a sample fluid supply bag, and a fluid collection bag wherein the column is provided for receiving the sample fluid from the sample fluid supply bag and for separating the target cells from the sample fluid and retaining the target cells.
  • the fluid collection bag is provided for subse ⁇ quently receiving the target cells from the column.
  • the cell separator includes an agitation assembly for agitating the contents of the column to assist in the release of target cells retained in the column.
  • the agitation assembly is responsive to a drive signal for varying the amount of agitation of the contents of the column to vary the rate at which the target cells are released.
  • the cell separator also includes a column sensor for providing a column signal indicative of the optical density of fluid flowing out of the column and into the fluid collection bag.
  • the cell separator includes a column valve that is responsive to a column valve control signal for selectively enabling the fluid coming out of the column to flow into the fluid collection bag.
  • a data processor is provided for controlling the operation of the cell separator. The data processor is responsive to the column signal for providing the drive signal and the column valve control signal to prevent inadequate concentrations of the target cells from being collected.
  • Figure 1 is an illustrative schematic diagram of a representative cell separator device for separating target particles from a sample fluid
  • Figure 2 is an illustrative schematic diagram of the cell separator of Figure 1 without the removable supply and collection bag and associated tubing;
  • Figure 3 is a side elevational view of a cell separator illustrating a pivotal bag holder
  • Figure 4 is a perspective view of an optical sensor of the cell separator.
  • Figure 5 is an illustrative schematic diagram of a control circuit for the cell separator
  • Figure 6 is a schematic diagram illustrating the operation of a valve of the present invention.
  • Figure 7 is a detailed illustrative diagram of the stirplate assembly of the cell separator
  • Figure 7A is a top plan view of the magnet table of the stirplate assembly
  • _ Figure 8 is a sectional diagram of the column for the ceE separator
  • Figure 9 is an exploded view of the column illustrated in Figure 8. Detailed Description of the Invention
  • the cell separator 100 includes a frame 102 having a base 104 and a support tower 106.
  • the support tower has a top 108 and bottom 110 wherein the bottom 110 is fixed to the base 104.
  • the base 104 is constructed for resting on a substantially horizontal surface such that the support tower 106 extends upright from the base 104. In this construction, the base 104 provides a substantially stable foundation for supporting the support tower 106.
  • the cell separator 100 also includes a bag holder 112 for receiving a sample fluid supply bag 114, and first and second fluid supply bags 116 and 118, respectively.
  • the sample fluid supply bag 114 is provided for supplying the sample fluid to the cell separator 100.
  • the first and second fluid supply bags 116 and 118 are provided for respectively supplying a wash solution and a protein solution to the cell separator 100, each solution for preparing the cell separator for the fluid separation, as will be discussed in more detail below.
  • the bag holder 112 includes a support rod 120, best illustrated in Figures 2 and 3, that is pivotally mounted to the top 108 of the support tower 106 for movement between an upright position wherein the support rod is substantially ahgned with the support tower, to a pivoted position, wherein the support rod is angled with respect to the support tower ( Figure 3).
  • the support rod is constructed for pivotal movement with respect to the support tower to enable the sample fluid supply bag 114 and the first and second fluid supply bags 116 and 118 to be easily mounted to the bag holder 112 by a user.
  • the fluid bags 114-118 may be both mounted and spiked by a user at substantially eye level.
  • the bag holder 112 is pivoted to the upright position to both move the fluid bags 114-118 out of the user's way, and to enable the user to manipulate other portions of the cell separator 100 at substantially eye level.
  • movement of the bag holder 112 with respect to the frame 102 is accomplished by pivoting the bag holder 112 with respect to the top 108 of the support tower 106, as described above.
  • the support tower 106 may be constructed to pivot about first and second pivot points, thereby enabling the bag holder 112 to be lowered with respect to the base 104.
  • the bag holder 112 may be slideably mounted upon the support tower 106, thereby enabling the bag holder 112 to be moveable with respect to the frame 102.
  • the bag holder 112 further includes a support beam 122 ( Figures 1 and 2) fixed to the support rod 120 and positioned substantially transverse to the support tower 106.
  • the support beam 122 includes a plurality of hooks 124-128 ( Figure 2) for receiving the fluid supply bags 114-118.
  • a fixed bag holder 130 is fixedly mounted to the top 108 of the support tower 106.
  • the fixed bag holder 130 includes a protruding hook 132 ( Figure 2) for receiving a wash fluid source bag 134.
  • the wash fluid source bag 134 is provided for supplying wash solution to the cell separator for cleansing the cell separator during a separation process, as will be discussed in more detail below.
  • a pre-column holder 136 is fixed to the support tower 106 intermediate the top 108 and bottom 110 thereof.
  • the pre-column holder 136 is provided for receiving a pre-column 138 ( Figure 1).
  • the pre-column 138 is provided for pre-filtering the sample fluid prior to the fluid separation to remove large particles and debris from the sample fluid.
  • the pre-column may comprise any of a variety of commercially available devices for pre-filtering the sample fluid. It will be apparent to those skilled in the art, however, that although the present invention is being described as including a pre-column 138, the pre- column 138 and pre-column holder 136 may be omitted from the cell separator 100 without departing from the invention.
  • a particularly novel aspect of the subject invention comprises a stirplate assembly 140 that is fixed to the support tower 106 intermediate the pre- column holder 136 and the bottom 110.
  • the stirplate assembly 140 includes a column holder 142 for receiving a column 144.
  • the column 144 is provided for separating the target particle from the sample fluid.
  • a presently preferred embodiment of the invention employs a column 144 that includes coated beads for positively selecting target cells from the sample fluid. As the sample fluid passes through the column 144, the target cells are retained within the column 144.
  • the stirplate assembly 140 cooperates with the column 144 to provide controlled agitation to the contents of the column 144.
  • the cell separator 100 further includes a sample sensor 148 and a column sensor 150 ( Figure 2) for sensing changes in optical density of fluid flowing in a tubing 152.
  • the sample sensor is fixed to the top 108 of the support tower 106 for sensing changes in optical density of fluid flowing from the sample fluid supply bag 114.
  • the column sensor 150 is fixed to the base 104 of the frame 102 for sensing changes in optical density of fluid flowing from the column 144.
  • Each of the sample sensor 148 and column sensor 150 comprises an optical sensor 400, illustrated in Figure 4.
  • the optical sensor 400 includes an optical transmitter 402 mounted in a sensor casing 403 and positioned for transmitting light to an optical receiver 404 (shown in phantom) also mounted in the sensor casing 403.
  • the optical transmitter 402 and receiver 404 are separated by a tube channel 406 constructed for receiving the fluid tubing 152 of the cell separator 100.
  • the optical sensor 400 is constructed for providing a sensor signal indicating the change in optical density of fluid flowing in the portion of the fluid tubing 152 positioned in the tube channel 406.
  • the optical sensor 400 may be readily constructed by one skilled in the art from commercially available products.
  • the optical sensor comprises an optical emitter model no. 0P133 as available from the Opteck Company, and an optical sensor model no. SPlOO-11-11-021 as available from the Silicon Detector Company both mounted in a suitable casing.
  • Other constructions for the optical sensor 400 will readily be apparent to those skilled in the art.
  • the sample sensor 148 is constructed for providing a sample sensor signal to indicate the change in optical density of the fluid coming out of the sample fluid supply bag 114.
  • the column sensor 150 is constructed for providing a column sensor signal to indicate the change in optical density of the fluid flowing from the column 144. Both the sample sensor signal and the column sensor signal are provided to a data processor assembly 500 ( Figure 5) for use in controlling the operation of the cell separator 100, as will be described in more detail below.
  • the cell separator 100 further includes a peristaltic pump 154 for pumping fluid between the plurality of fluid bags 114-118 and 134 and the fluid tubing 152.
  • the peristaltic pump is responsive to a pump control signal provided by the data processor assembly 500 ( Figure 5) for controlling the speed and direction of flow of fluid in the fluid tubing 152.
  • the peristaltic pump 154 is further constructed for providing a pump speed signal to the data processor 500 ( Figure 5).
  • the pump speed signal is indicative of the speed and direction that fluid is being pumped through the fluid tubing.
  • An appropriate peristaltic pump for performing the above-described operation may be readily constructed by one skilled in the art.
  • the peristaltic pump comprises a Cavro 4708-5 peristaltic pump as provided by Cavro Scientific Instruments, Inc. (Sunnyvale, California). It will be apparent, however, that other apparatus for providing the functions of the peristaltic pump may readily be substituted for the Cavro pump used in a presently preferred embodiment of the invention.
  • the cell separator 100 includes a plurality of valves 156A-L ( Figure
  • Each of the valves 156 includes a solenoid (not shown) and plunger 600 ( Figure 6) separated by a valve channel 602 sized to receive the fluid tubing 152.
  • Each valve 156 is responsive to a respective valve control signal for displacing the plunger 600 to collapse the fluid tubing and thereby prevent the flow of fluid through the valve 156.
  • the plurality of valves 156A-L are positioned to receive respective portions of the fluid tubing 152, thereby to define a plurality of fluid flow paths between the fluid bags.
  • the data processor assembly 500 is constructed to provide the plurality of valve control signals for controlling the path that the fluid flows through the fluid tubing 152, as will be discussed in more detail below.
  • the cell separator 100 further includes a data processor assembly
  • the data processor includes a microprocessor
  • the microprocessor 502 for controlling the operation of the data processor assembly 500.
  • the microprocessor 502 is coupled to a user interface 504 for providing information to and receiving information from a user of the cell separator.
  • the user interface for providing information to and receiving information from a user of the cell separator.
  • data processor assembly 500 includes a display 506 and a keyboard 508 for respectively providing information to and receiving information from a user of the cell separator.
  • the microprocessor 502 is also coupled to memory 510 that is provided- for storing programming instructions and data for controlling the operation of the microprocessor 502.
  • the microprocessor 502 is coupled to an interface 512 for interfacing the data processor assembly 500 with the sample sensor 148, the column sensor 150, the peristaltic pump 154, the plurality of valves 156 and the stirplate assembly 140.
  • data processor assembly 500 comprises a personal computer as is commercially available.
  • the stirplate assembly 140 includes a housing 700 having mounted therein a rotating table assembly 702 for generating a moving magnetic field. More particularly, with reference to Figure 7A, the table assembly 702 comprises a substantially flat circular magnet table 704 having mounted thereon first and second magnets 706 and 708. The magnet table 704 is mounted upon a bearing assembly 710 that rotatably supports the magnet table 704.
  • the stirplate further includes an electric motor 712 mounted exterior to the stirplate housing 700.
  • the electric motor 712 includes a drive wheel 714 coupled to the electric motor 712 via a shaft 716.
  • the electric motor 712 is responsive to a drive signal received from the data processor assembly 500 for rotating the shaft 716 and drive wheel 714.
  • the electric motor 712 comprises a stepper motor responsive to digital signal for incrementally rotating the shaft 716. It will be apparent, however, to those skilled in the art, that other motors may be readily substituted for the electric motor 712.
  • a drive belt 718 is coupled to the drive wheel 714 and the magnet table 704 for transferring rotational movement from the electric motor 712 to the magnet table 704.
  • An optical encoder assembly 734 is optically coupled to an encoding wheel 736 of the magnet table 704 for providing a table speed signal indicative of the speed of rotation of the magnet table 704.
  • the table speed signal is provided to the data processor assembly 500 to provide feedback for providing the drive signal, as will be discussed below.
  • stirplate assembly 140 is described herein as generating a moving magnetic field by rotating the first and second magnets 706 and 708, other apparatus, e.g., electromagnetic field generating apparatus, may be provided for generating a moving magnetic field. Further, as will become apparent below, it may be desirable in some applications to create the moving magnetic field by providing other motion to the field generating magnets, e.g., linear motion.
  • the stirplate assembly 140 also includes a positioning portion 720 mounted to the exterior of the housing 700 on the top thereof, for fixedly receiving the column 144.
  • the positioning portion is fixed to the housing 700 proximate the magnet table 704 so that the moving magnetic field is magnetically coupled to the column 144.
  • a seat portion 722 is constructed to matably receive the column 144 ( Figure 8) to position the column proximate the magnet table 704 so that the moving magnetic field is magnetically coupled to the column 144, as will be described in more detail below.
  • the positioning portion further includes a gripping portion 724 fixed to the seat portion 722 and constructed to engage the exterior of a column to position the column within the stirplate.
  • the gripping portion 724 includes a plurality of extending finger portions 726 each extending upward from the seat portion 722 and ending in a contact portion 728 positioned for contacting the perimeter of the column 144.
  • the stirplate assembly further includes a position sensor 730 for sensing when the column is positioned in the positioning portion 720 of the stirplate assembly 140.
  • the position sensor 730 comprises a spring actuated switch 732 positioned for engaging the periphery of the column 144 when the column is positioned within the positioning portion 720.
  • the switch 732 is constructed to move linearly inward when the column 144 is properly positioned, to close an electrical contact and thereby provide a column position signal to the data processor assembly 500.
  • the position sensor 730 further comprises a Hall effect sensor 800 (best illustrated in Figure 8) that is constructed for sensing changes in the magnetic field to thereby determine the position of the first and second magnets 706 and 708 and for providing a stirbar position signal to the data processor assembly 500, indicative of the sensed change in magnetic field.
  • the data processor assembly 500 is responsive to the stirbar position signal and the table speed signal for modulating the drive signal provided to the motor 712 to thereby control the variation in the moving magnetic field.
  • both signals are not required to adequately control the speed of the magnet table 704 under many circumstances.
  • the stirplate assembly includes a seat portion 722 and a gripping portion 720 for fixedly receiving and positioning the column 144.
  • the column 144 includes a top 802 and a bottom 804, each separated by a cylinder 806.
  • the column includes an agitation assembly 808 that is responsive to the moving magnetic field created by the stirplate assembly 140 for agitating the contents of the column 144.
  • the position sensor 730 determines the variation in magnetic field caused by movement of the stirplate magnets 706 and 708 so that the stirbar position signal is indicative of the speed of movement of the agitation assembly 808.
  • the data processor assembly 500 responds to the stirbar position signal provided by the position sensor 730 to modulate the drive signal provided to the stirplate assembly 140. Accordingly, the data processor 500 is capable of precisely controlling the speed and direction of movement of the agitation assembly and, thereby, precisely controlling the agitation provided to the contents of the column 144.
  • the tubing 152 that is coupled to the top 802 and bottom 804 of the column 144 includes first and second pressure sensors 810 and 812, respectively.
  • the pressure sensors 810 and 812 each provide pressure signals to the data processor assembly 500.
  • the data processor 500 is capable of deterrnining the pressure differential in the column intermediate the first and second pressure sensors 810 and 812.
  • the data processor assembly 500 responds to the determined pressure in the column 144 to control the overall operation of the cell separator 100, as will be discussed in more detail below.
  • the cylinder 806 includes a top portion 814, a bottom portion 816, and an inner channel 818 extending from the top portion to the bottom portion.
  • the top and bottom portions 814 and 816 are open so that the channel 818 extends through the cylinder 806.
  • the cylinder 806 includes a top portion 814, a bottom portion 816, and an inner channel 818 extending from the top portion to the bottom portion.
  • the top and bottom portions 814 and 816 are open so that the channel 818 extends through the cylinder 806.
  • the cylinder 806 includes a top portion 814, a bottom portion 816, and an inner channel 818 extending from the top portion to the bottom portion.
  • the top and bottom portions 814 and 816 are open so that the channel 818 extends through the cylinder 806.
  • the cylinder 806 includes a top portion 814, a bottom portion 816, and an inner channel 818 extending from the top portion to the bottom portion.
  • the top and bottom portions 814 and 816 are open so that
  • lock inlet 820 includes a lock inlet 820 and a mating lock inlet cap 822 as is known in the art.
  • the top portion 802 and bottom portion 804 each include a rim 824 fixed to a base 826 of a hollow frustum 828 and a tube stem 830 fixed to the frustum 828 opposite the rim 824.
  • the tube stem 830 is of the type for receivmg a lock cap for sealing the column prior to the coupling of the tubing 152 to the column 144.
  • the rim 824 has a substantially circular flange 832 fixed to the base 826 and a substantially cylindrical skirt 834 fixed to the flange 832.
  • the tube stem 830 extends outwardly from the frustum 828 and mcludes an inner channel for conducting liquid into and out of the top 802 and bottom 804.
  • Each of the top and bottom further include a plurality of support ribs 836 extendmg radially inward from the rim 824 toward the tube stem to provide an inner frustum channel having fluid flow passageways between adjacent ones of the plurality of support ribs 836 so that fluid can flow between the base of the frustum and the inner channel of the tube stem 830.
  • the rims 824 of the top and bottom 802 and 804, respectively, are sealed to the top and bottom portion 814 and 816 of the cylinder with the tube stems 830 extending outward from the cylinder 806.
  • First and second substantially planar membranes 838 and 840 respectively, each include a substantially circular perimeter to mate with the flanges 832 of the top and bottom.
  • the first and second membranes 838 and 840 are constructed to permit the flow of particles less than a predetermined size and to prevent the flow of particles greater than the predetermined size.
  • the membranes 838 and 840 are constructed of a size to prevent the flow of the substrate beads and thereby capture and retain the substrate within the cylinder 806.
  • a cylinder insert 842 is positioned intermediate the second membrane 840 and the bottom portion 816 of the cylinder.
  • the cylinder insert 842 includes a plurality of base support ribs 844 extending across the diameter of the channel 818 and intersecting substantially at the center thereof to define a base support 848 for a shaft 850.
  • the shaft 850 extends inward of and substantially parallel to the cylinder 806.
  • the shaft includes a base portion 852 fixed to the base support, an extending portion 854 opposite the base portion, and a recessed portion 856 intermediate the base portion and the extending portion.
  • the combination of the cylinder, the first and second membranes, the cylinder insert, and the top and bottom form the column 144 having a fluid flow channel defined from the tube stem 830 of the top 802 through the cylinder 806 to the tube stem 830 of the bottom 804.
  • the agitation assembly 808 mounted within the channel 818 of the column comprises first and second stirbar portions 858 and 860 that are constructed to be fixed together to define a stirbar 862.
  • the stirbar 862 includes a mounting portion 864 having first and second magnet sections 866 and 868 extending radially outward therefrom. Each of the first and second magnet sections comprises a stirbar magnet 870 and 872, respectively, housed in a substantially cylindrical, nonmagnetic casing.
  • the mounting portion 864 has a through hole of diameter larger than the diameter of the shaft 850.
  • the mounting portion includes first and second projections 874 on opposite sides thereof extending inward of the through hole.
  • the mounting portion is mounted to the recessed portion 856 of the shaft so that the mounting portion rotates freely about the shaft and so that the movement of the mounting portion linearly along the shaft is limited by the engagement of the first and second projections 874 with the recess portion of the shaft 850.
  • the stirbar 862 further includes a sleeve portion 876 having an interior chamber of diameter greater than the diameter of the extending portion 854 of the shaft 850.
  • the sleeve portion 876 is fixed to the mounting portion 864 so that the extending portion 854 is positioned within the interior chamber and so that the sleeve portion rotates freely about the extending portion.
  • the stirbar 862 further includes first and second propeller blades 878 and 880, respectively.
  • the first and second propeller blades are substantially planar in configuration and are fixed to the sleeve portion 876 so that the lengths of the first and second propeller blades extend radially outward from the sleeve portion and so that the width of the first and second propeller blades is positioned at a diagonal with respect to the axis of rotation of the sleeve portion.
  • the sleeve portion is fixed to the mounting portion so that the first and second propeller blades are substantially perpendicular to the first and second magnet sections 866 and 868.
  • the first and second stirplate magnets 706 and 708 are magnetically coupled to the stirbar magnets 870 and 872 of the stirbar 862. Accordingly, rotation of the magnets 706 and 708 results in rotation of the stirbar 862. Since the speed of rotation of the magnets 706 and 708 is controlled by the data processor assembly 500, rotation of the stirbar 862 is similarly controlled by the data processor assembly 500. It will be apparent to those skilled in the art that rotation of the first and second stirbar magnets 870 and 872 will impact the change in magnetic field sensed by the Hall effect sensor 800 ( Figure 8).
  • the data processor assembly 500 may be constructed to monitor the stirbar position signal provided by the Hall effect sensor 800 to determine whether the stirbar magnets 870 and 872 are magnetically coupled to the stirplate magnets 706 and 708. Essentially, this monitoring is to determine whether the change in magnetic field is as expected, given the speed of rotation of the magnetic table 704, as determined by the table speed signal.
  • the present stirbar apparatus mounted for rotation within the column, permits control over the agitation superior to that may be attained using stirbars that are permitted free movement within the column.
  • the cell separator 100 permits substantially hands-free operation by a relatively unskilled operator.
  • the fluid bags 114-118 and 134, along with the tubing 152 and column 144, are provided as disposable apparatus constructed for use during only a single separation process. In operation, the user of the ceE separator 100 pivots the bag holder
  • the bag holder 112 to mount the fluid bags thereon and to spike the fluid bag for operation.
  • the bag holder 112 is then returned to the upright position and the tubing properly placed within the sensors 148 and 150 and the valves 156.
  • the data processor assembly 500 selectively opens and closes the valves 156 to permit wash fluid to flow from the wash fluid bag 134 sequentially through the valves 156H, 156J, 156G, 156E, 156C and 156A This fluid flow acts to remove air from the tubing 152 and column 144 and to cleanse the tubing of impurities that may be in the tubing from its manufacture.
  • the data processor assembly 500 controls the valves 156 to prime the tubing by allowing fluid to flow from the second fluid supply bag 118 through the valve 156A, the valve 156D, the pre-column 138, the valve 156, the column 144, the valve 156L and into a waste bag 158.
  • the flow of fluid in this manner primes the column and tubing with a protein solution selected to prevent substantial bonding of the target cells to the tubing.
  • the microprocessor controls the valves to permit fluid to flow from the first fluid supply bag 116 through the valve 156C, the pre-column 138, the column 144, the valve 156L and into the waste bag 158.
  • fluid is permitted to flow from the wash fluid source bag 134 through the valve 156F, the column 144, and the valve 156L and into the waste bag 158.
  • This fluid flow permits rinsing of the tubing and column to remove excess protein and to further wash residual material that may be remaimng in the tubing and column from manufacture.
  • the cell separator 100 After the cell separator 100 has primed the tubing, it runs the cell separation process. Initially, the data processor assembly 500 opens the valves 156C and 156B to wet the tubing and filter, coupling the sample bag 114 to the tubing 152. Thereafter, the valves 156B, 156G, and 156L are controlled with the peristaltic pump to permit slow loading of the sample via the column. During this phase, the sample fluid is slowly permitted to pass through the column so that the target cells may bind with the substrate of the column 144. The unwanted material of the sample fluid is discarded in the waste bag 156.
  • the data processor assembly 500 monitors the sample sensor signal and the column sensor signal to determine whether all of the sample fluid has been provided and to determine whether a significant amount of target cells are being discarded in the waste bag 156. If either of these events occur, the data processor assembly 500 will discontinue the loading step and move to another portion of the cell separation.
  • the data processor assembly 500 also monitors the pressure signals provided by the pressure sensors 810 and 812 to determine whether the pressure across the column 144 is above a predetermined maximum pressure. If the pressure increases beyond a maximum, the data processor assembly 500 may reduce the pressure by slowing the pump speed of the peristaltic pump 154. Other alternative steps may be taken in catastrophic cases by the user to further alleviate excess pressure within the column 144. As an example, the user may actually reverse the flow of fluid through the column from a wash bag 160 to the wash fluid source bag 144 to aid in dislodging unwanted materials so that they may be removed from the column to decrease the overall pressure within the column.
  • the data processor assembly 500 monitors the sample sensor signal provided by the sample sensor 148 to determine when the sample fluid supply is empty. Those skilled in the art will appreciate that the optical density of the fluid flowing past the sample sensor 148 will change dramatically at the instant the last portion of the sample fluid passes by the sample sensor 148. At that point, the microprocessor assembly 500 determines that no further sample fluid is available, and that the column should be emptied.
  • the microprocessor assembly 500 will wash the column to remove non- specifically bound portions of the sample fluid.
  • the valves 156 will be controlled to permit fluid to flow from the wash fluid source bag 134 to the waste bag 158.
  • the microprocessor assembly 500 may be controlled to provide very light agitation to the column by providing a drive signal to the stirplate assembly 140 to slowly rotate the stirbar 862 of the column 144.
  • no agitation is provided during the column wash step.
  • the target cells are eluted from the column.
  • the microprocessor assembly 500 controls the valves 156F, 156J, and 1561 to permit fluid to flow from the wash fluid source bag 134 through the column 144 to a stem cell collection bag 162.
  • the microprocessor controls the agitation provided to the column by the stirplate assembly 140 and the stirbar 162 to optimize the concentration of target cells being collected in the collection bag 162.
  • the microprocessor assembly 500 monitors the column sensor 152 to determine the optical density of the target cells being collected, and thereby maximize concentration of the target cells.
  • the microprocessor assembly 500 may increase the amount of target cells being collected by either increasing the amount of agitation provided to the column or by decreasing the speed at which the peristaltic pump permits target cells to be withdrawn from the column.

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Abstract

Un séparateur de cellules perfectionné comporte un dispositif de commande automatique concernant le processus de séparation. Des valves réagissent à un dispositif de traitement de données qui régit le trajet du fluide au travers du séparateur de cellules. Des capteurs fournissent des signaux indiquant la densité du fluide qui passe par ce séparateur. Le microprocesseur réagit aux signaux des capteurs afin de commander le flux et le fonctionnement du séparateur de cellules. Une pompe péristaltique obéit au microprocesseur et commande la vitesse et la direction du fluide qui s'écoule dans l'appareil. Un plateau d'agitation obéit à un signal d'entraînement provenant du dispositif de traitement de données et agite de manière contrôlée le contenu d'une colonne. Le dispositif de traitement de données réagit en outre aux informations provenant des capteurs en envoyant des signaux de commande concernant les valves et la pompe pour régir ainsi la concentration de cellules requises qui sont collectées. Ce séparateur de cellules perfectionné comporte aussi un plateau d'agitation amélioré dont la colonne reçoit une baguette d'agitation tournante. Cette dernière comprend un aimant et un axe qui part de celui-ci vers l'extérieur et porte deux pales d'hélice, ce qui permet d'augmenter l'agitation conférée au contenu de la colonne par la baguette d'agitation. Le plateau d'agitation est conçu de manière à fournir un champ magnétique tournant par couplage magnétique avec les aimants de la baguette d'agitation, ce qui permet d'effectuer cette dernière. Le plateau d'agitation comporte un capteur à effect Hall qui fournit un signal de position de baguette d'agitation indiquant une variation du champ magnétique due à la rotation des aimants. Le processeur de données du séparateur de cellules réagit à ce signal de position de baguette d'agitation afin de commander la variation du champ magnétique mobile, ce qui permet de contrôler la vitesse de rotation de la baguette d'agitation.
PCT/US1992/008988 1991-10-23 1992-10-23 Appareil et procede ameliores concernant la separation de cellules Ceased WO1993008258A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP5507895A JP2774195B2 (ja) 1991-10-23 1992-10-23 細胞分離のための改良された装置及び方法
EP92923299A EP0610391B1 (fr) 1991-10-23 1992-10-23 Appareil et procede ameliores concernant la separation de cellules
DE69215381T DE69215381T2 (de) 1991-10-23 1992-10-23 Verbesserter apparat und verfahren zur trennung von zellen

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US780,750 1991-10-23
US07/780,750 US5240856A (en) 1991-10-23 1991-10-23 Apparatus for cell separation

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WO1993008258A1 true WO1993008258A1 (fr) 1993-04-29

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EP (2) EP0610391B1 (fr)
JP (2) JP2774195B2 (fr)
AT (1) ATE145425T1 (fr)
CA (1) CA2122035C (fr)
DE (1) DE69215381T2 (fr)
DK (1) DK0610391T3 (fr)
ES (1) ES2094378T3 (fr)
WO (1) WO1993008258A1 (fr)

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EP0610391B1 (fr) 1996-11-20
EP0610391A1 (fr) 1994-08-17
ES2094378T3 (es) 1997-01-16
JPH07500664A (ja) 1995-01-19
DE69215381T2 (de) 1997-03-13
EP0721011A1 (fr) 1996-07-10
DK0610391T3 (da) 1997-04-14
US5684712A (en) 1997-11-04
DE69215381D1 (de) 1997-01-02
JP2774195B2 (ja) 1998-07-09
ATE145425T1 (de) 1996-12-15
CA2122035C (fr) 1997-07-15
JPH1082A (ja) 1998-01-06
US5240856A (en) 1993-08-31

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